Remimazolam Anaphylaxis during Induction of General Anesthesia Confirmed by Provocation Test—A Case Report and Literature Review

Background: Remimazolam besylate, a newly developed drug, is linked to various anaphylaxis cases. We present a case of remimazolam anaphylaxis confirmed using a provocation test. Case: A 51-year-old female patient was scheduled for humeral pinning. General anesthesia was induced using remimazolam, rocuronium, and remifentanil. After tracheal intubation, the patient experienced decreased blood pressure, increased heart rate, and a systemic rash. Epinephrine was administered repeatedly, and the patient’s vital signs stabilized. Acute phase tryptase levels were within normal limits. After four weeks, intradermal test results were negative. When remimazolam was administered intravenously for the provocation test, facial swelling, flushing, and coughing occurred, which improved with epinephrine. The culprit drug was identified as remimazolam using a provocation test. Conclusions: When anaphylaxis occurs during anesthesia induction, remimazolam should not be ruled out as the causative drug. If the skin test result for remimazolam is negative, a provocation test should be considered. The provocation test should be initiated cautiously at a low dose under careful patient monitoring.


Introduction
Perioperative anaphylaxis occurs in approximately 1 in 10,000-20,000 cases of general anesthesia, with a 3-9% mortality rate [1].Anaphylaxis is a severe, acute type 1 hypersensitivity reaction that requires immediate epinephrine, real-time blood pressure monitoring, airway security, and fluid administration [2].Remimazolam besylate is a relatively recently developed ultra-short-acting benzodiazepine used for the induction and maintenance of sedation and general anesthesia [3].Its use is gradually increasing owing to its rapid onset, offset, and hemodynamic stability [4].Similar to midazolam, the effects of remimazolam can be reversed using flumazenil, and it offers a rapid recovery from general anesthesia [5].It causes less respiratory depression compared to traditional sedative drugs such as propofol [6,7].Additionally, while remimazolam is classified as a benzodiazepine, previous studies have reported that it does not increase the risk of postoperative delirium [8,9].Although the safety of remimazolam has been evaluated, various cases of remimazolam anaphylaxis have been recently reported [10][11][12][13][14][15].
In this case report, anaphylaxis occurred during the induction of general anesthesia.Subsequent allergy tests showed negative results for all intradermal tests.However, a provocation test confirmed remimazolam as the causative drug with a positive result.

Case Report
Written informed consent was obtained from the patient for this case report.Ethical approval was obtained from the Institutional Review Board of Kyung Hee University Hospital (KHUH 2023-10-003) on 5 October 2023.A 51-year-old female patient (height 170 cm; weight 52 kg) was scheduled to undergo closed humeral reduction and pinning under general anesthesia.The patient had a history of allergies after using an oral topical anesthetic spray during a gastroscopy at another hospital.Because of the history that occurred at another hospital long ago, detailed medical records could not be confirmed, and the topical anesthetic was presumed to be lidocaine.The patient stated that urticaria and an itching sensation appeared on the upper body.She had no other medical history, and there were no abnormal findings in the pre-anesthetic patient evaluation, including laboratory and imaging tests and electrocardiography (ECG).
After admission to the operating room, the heart rate (HR) and rhythm were monitored using a 3-lead ECG.Standard monitoring, including noninvasive blood pressure (BP) measurement using an arm cuff and peripheral oxygen saturation (SpO 2 ), was also started.The initial BP was 113/64 mmHg, and the HR was 57 beats/min (bpm).Preoxygenation was performed by supplying 6 L of 100% oxygen and 0.2 mg of glycopyrrolate as an anticholinergic and 0.075 mg of palonosetron as an antiemetic were administered intravenously (IV).Remimazolam was prepared as an anesthetic agent at 1 mg/mL and administered at a rate of 12 mg/kg/h for 1 min to induce anesthesia; 10 mg (0.2 mg/kg) were administered.After confirming loss of consciousness, rocuronium 40 mg (0.8 mg/kg) was administered as a neuromuscular blocking agent.Following the administration of rocuronium, the patient developed a skin rash on the chest wall.However, the rash subsided after the administration of 10 mg of dexamethasone.After administration of remifentanil 0.5 µg/kg, tracheal intubation was performed.Immediately after tracheal intubation, noninvasive BP was 32/18 mmHg, HR was 102 bpm, and the skin rash on the entire body worsened, accompanied by swelling.Other than hypotension and tachycardia, no other ECG changes were observed, and transesophageal echocardiography could not be performed due to problems with equipment availability at the institute.No antibiotics had been given; an emergency alarm was activated in the operating room due to suspected rocuronium-induced anaphylaxis, and medical staff were called for assistance.Invasive BP was monitored through radial artery cannulation, and epinephrine was administered while the fluid was loaded through a peripheral 16-gauge IV cannulation.Blood samples were collected through the arterial line immediately after radial artery cannulation; subsequently, arterial blood gas analysis (ABGA) and an acute phase tryptase test were performed.There were no unusual findings in the ABGA results (pH 7.359, PaCO 2 44.5 mmHg, PaO 2 204.2 mmHg, HCO 3 − 23.7 mmol/L, base excess −2.1 mmol/L, lactate 1.73 mmol/L).After total administration of epinephrine 500 µg IV and crystalloid 1000 mL, the skin rash and BP normalized, and central venous cannulation was performed at the right internal jugular vein.Subsequently, hypotension was observed, and epinephrine was administered at 0.2 µg/kg/min IV.While managing anaphylaxis, the peak airway pressure on the ventilator did not increase, chest auscultation was normal, and SpO 2 was maintained at 100%.After confirming no signs of airway obstruction, sugammadex 200 mg IV was administered as a neuromuscular blockade reversal agent.Spontaneous breathing was restored, and tracheal extubation was performed.The surgery was canceled, and the patient was discharged to the intensive care unit (ICU).A chest radiography was performed in the ICU and the findings were unremarkable (Supplementary Figure S1).
Within the target of 20% of the initial systolic BP, the epinephrine dose was reduced to 0.1 µg/kg/min after 9 h, and finally, it was discontinued after 40 h.Additional oxygen supply was stopped 17 h after the onset of anaphylaxis.The patient did not complain of respiratory symptoms such as dyspnea when breathing room air.Twenty-six hours after the onset of anaphylaxis, the patient was transferred to the general ward and discharged three days later.The acute phase tryptase level, measured after radial artery cannulation, was 3.9 µg/L.
Four weeks after the anaphylaxis, the patient was readmitted to the allergy department for allergy testing.Intradermal tests were performed with glycopyrrolate, palonosetron, remimazolam, rocuronium, and remifentanil, all administered during anesthesia induction.Additionally, midazolam, which is structurally similar to remimazolam, was evaluated.Intradermal test results were negative for all drugs.A provocation test was performed to exclude the drug as the cause of anaphylaxis.When midazolam was diluted 1:100 in normal saline and administered intravenously at 1 mL, no anaphylactoid symptoms were induced.When remimazolam was diluted to 1 mg/mL in normal saline and administered intravenously at 1 mL, facial edema, rash, and cough occurred 4 min later, and an allergic reaction was observed as SpO 2 decreased from 99% to 90%.Symptoms improved after IV epinephrine administration.Based on this provocation test, remimazolam was identified as the drug that caused anaphylaxis.

Discussion
Diagnosing perioperative anaphylaxis can be challenging due to the variety of drugs used, including anesthetics, antibiotics, neuromuscular blockers, and latex.Recently, cases of remimazolam-induced anaphylaxis have been consistently reported.To the best of our knowledge, 11 cases have been reported in six research articles (Table 1) [10][11][12][13][14][15].Compared with previous cases, the characteristic feature of this case was that the drug for anaphylaxis was finally identified as remimazolam in the provocation test.Generally, in cases of anaphylaxis that occur during anesthesia induction, neuromuscular blockers or antibiotics are most commonly suspected.In previous studies that reported perioperative anaphylaxis, approximately 25-60% and 20-50% of cases were caused by neuromuscular blockers and antibiotics, respectively [16,17].The present case occurred before antibiotic administration, and we suspected rocuronium-induced anaphylaxis before the allergy test.Through a meticulous approach during the allergy test, we identified remimazolam as the causative drug for anaphylaxis following a provocation test.Therefore, even if the intradermal test was negative for remimazolam, a provocation test was recommended for final confirmation.In further studies, protocols for intradermal tests and provocation tests with remimazolam should be established.We have summarized the characteristics of remimazolam anaphylaxis by reviewing 12 case reports, including the present case (Table 1).First, most cases of anaphylaxis occurred at the time of induction of general anesthesia, before and after tracheal intubation, when a relatively excessive dose of remimazolam was administered.Therefore, clinicians should monitor patients more carefully when inducing general anesthesia using remimazolam, and the drug should be administered slowly over 1-2 min according to the pharmaceutical label indications.Symptoms of anaphylaxis were reviewed separately for the skin, cardiovascular, and respiratory systems [18].Skin symptoms have been reported in approximately half of these cases.Cardiovascular symptoms have been reported in most cases with a decrease in BP.Low BP usually occurs at a systolic BP of 30-40 mmHg, and cardiac arrest occurs in severe cases [13,14].Respiratory symptoms such as hypoxia and airway edema were reported in half of the cases.Respiratory symptoms may tend to be underestimated because most patients are already tracheally intubated.In the present case, no respiratory symptoms occurred at the time of anaphylaxis due to tracheal intubation.However, coughing and hypoxia occurred during the provocation test.For the treatment of anaphylaxis, epinephrine was administered in all cases, and a bolus dose of approximately 250-750 µg IV was administered, except for the extreme values.During anaphylactic management, severe hypertension caused by excessive epinephrine administration may be fatal [19].The epinephrine dose must be determined through close observation of the patient's vital signs.The acute phase tryptase levels were significantly higher than the baseline values in the majority of cases, excluding error cases in laboratory tests.Serum tryptase levels are reported to be significantly increased when acute tryptase > ((1.2 × baseline tryptase) + 2) µg/L [20].In the present case, baseline tryptase levels could not be evaluated because of problems with blood sample handling.However, compared with the acute phase tryptase in other cases, the level in the present case was substantially low.Additionally, even when considering the suggested normal range of tryptase in previous studies as 2.1-9.0 µg/L [12], the acute phase tryptase level of the present case may not have been elevated.Failure to measure the baseline tryptase level is a limitation of the present case.Both acute phase and baseline tryptase levels should be measured, and anaphylaxis cannot be completely ruled out even if the acute phase tryptase level is not significantly elevated, as observed in the present case.
Tsurumi et al. [10] reported that anaphylaxis is induced by a cross-reaction between midazolam and remimazolam.In the present case, allergy testing was performed using midazolam to evaluate the possibility of cross-reactivity.Both intradermal and provocation tests for midazolam were negative.Because the allergy test was negative for midazolam, which has a structure similar to that of remimazolam, the possibility of anaphylaxis induced by the additive dextran 40 rather than remimazolam itself can be considered.Dextran 40 can induce non-IgE-mediated anaphylaxis and may result in negative skin tests [21].Previous case reports have suggested that in patients with negative skin tests, it is worth considering whether the causative agent of anaphylaxis was dextran 40 rather than remimazolam.Sander et al. [22], in a review article, also reported that anaphylaxis caused by remimazolam might be related to a non-IgE-mediated effect of the excipient dextran-40.Therefore, when conducting allergy tests, the inclusion of remimazolam and dextran 40 is recommended.
This case report had several limitations.First, baseline serum tryptase levels were not evaluated because of blood sample handling issues.In most cases, an increase in tryptase is determined by comparing the acute phase with the baseline value, rather than a specific normal range.Therefore, it is necessary to test the baseline serum tryptase level.However, in the present case, the acute phase tryptase level was much lower than that in other cases, and a significant increase was not confirmed even when the baseline value was measured.Second, because of the lack of agents, allergy tests cannot be performed only for dextran 40.If remimazolam-induced anaphylaxis is suspected, an allergy test for the additive dextran 40 should be performed.Third, a protocol for the provocation test with remimazolam has not been established.In this case, severe allergic symptoms developed during the provocation test.Demoly et al. [23] reported that a previous life-threatening

Table 1 .
Summary of case reports of remimazolam-induced anaphylaxis.